2-alkylidene-4-oxothiazolidine s-oxides: synthesis, structure and chemical transformations

Sulfoksidna funkcionalna grupa je česta u farmakološki značajnim jedinjenjima,a literaturni podaci ukazuju na to da uvođenje ove funkcionalne grupe u tiazolidinskiprsten može da poveća biološku aktivnost molekula koji sadrže ovaj strukturnifragment. Iako je sinteza, hemijsko ponašanje i biološka aktivnost 4-oksotiazolidinskihS-oksida predmet interesovanja velikog broja hemičara, podaci o stereohemijskomnivou strukture često nedostaju ili su nedovoljno jasno predstavljeni. S tim u vezi,detaljno ispitivanje reakcije oksidacije sumpora kod 2-alkiliden-4-oksotiazolidina, kao istereohemijska karakterizacija proizvoda od značaja su za utvrđivanje stepena i uzrokadiastereoselektivnosti pri oksidaciji različitih cikličnih i acikličnih organskih sulfida kojiposeduju stereogeni centar u susedstvu atoma sumpora.U skladu sa postavljenim ciljevima, nakon optimizacije reakcionih uslovasintetizovana je serija 4-oksotiazolidinskih S-oksida oksidacijom atoma sumpora kod 2-alkiliden-4-oksotiazolidina koji se razlikuju po supstituentima vezanim za egzocikličnudvostruku vezu, atom azota i C(5) položaj prstena. Oksidacijom pomoću m-CPBA 5-supstituisani 4-oksotiazolidinski sulfoksidi dobijeni su kao smese dva diastereomera uzumerenu diastereoselektivnost koja varira od 57-74% diastereomernog viška.Relativna konfiguracija 5-supstituisanih sulfoksida određena je korelacijomeksperimentalno i teorijski dobijenih NMR podataka. Strukture polaznih 2-alkiliden-4-oksotiazolidina i sintetizovanih tiazolidinonskih S-oksida optimizovane su na DFTnivou, korišćenjem B3LYP funkcije i 6-31G* baznog seta, u gasnoj fazi. NMRhemijska pomeranja izračunata su primenom GIAO metode, na istom nivou teorije, ugasnoj fazi i u prisustvu rastvarača.Na osnovu eksperimentalnih i računski dobijenih rezultata utvđeno je da jeproces oksidacije 5-supstituisanih 2-alkiliden-4-oksotiazolidina kinetički kontrolisan,pri čemu lakšim prilaskom reagensa (m-CPBA) sa sterno manje zaštićene strane u većojkoličini nastaje manje stabilan anti-izomer. U toku obrade reakcione smese dolazi douravnotežavanja pa se kao krajni proizvod dobijaju smese obogaćene termodinamičkifavorizovanim sin-izomerom. Veća stabilnost sin-izomera posledica jeintramolekulskog C(5')H···OS 1,5-vodoničnog vezivanja i jače σC(5)-H → σ*S-Ohiperkonjugacione interakcije nasuprot slabijoj σC(5)-C(5') → σ*S-O interakciji kod antiizomera...The sulfoxide functional group is common in pharmaceutically important compoundsand many sulfoxides are known to have high biological activity. Sulfur oxidation of 4-oxothiazolidine may result in more potent compounds. Although synthesis, chemicalbehavior, and biological activity of 4-oxothiazolidine S-oxides have been frequentlyinvestigated, no information concerning their diastereomeric purity or stereochemicalstructure has been given usually. Having this in mind, detailed investigation of 2-alkylidene-4-oxothiazolidine oxidation reaction and stereochemical characterization of sulfoxideproducts should be of interest for further investigations of sulfur oxidation in acyclic andcyclic sulfides having stereogenic center adjacent to sulfur atom.In accordance with the aims of this thesis, after initial screening of different oxidizingagents, a series of 5-substituted and 5-unsubstituted 2-alkylidene-4-oxothiazolidine S-oxideswere synthesized by the sulfur-oxidation of the parent sulfides with m-CPBA. The productswere obtained in good yields, 51-95%, and with moderate diastereoselectivity in case of 5-substituted derivatives (de 54-74%).The relative configuration of 5-substituted sulfoxides was determined by means ofNMR spectroscopy and DFT theoretical calculations. The structures of starting 2-alkylidene-4-oxothiazolidines and sulfoxides were optimized in the gas phase at the B3LYP/6-31G∗level. NMR chemical shifts were calculated by using the GIAO method, at the same level oftheory in the gas phase and with inclusion of solvent.On the basis of experimental and computational results it was found that thestereochemistry of the oxidation step was kinetically controlled by the reagent (m-CPBA)approach from the sterically less hindered side. Less stable anti-isomer was initially formed,but it underwent epimerization to the mixture enriched in the more stable syn-isomer, duringthe work-up process. The higher stability of syn-isomers was ascribed to the strongerhyperconjugative σC(5)−H → σ∗S−O interaction versus the weaker σ C(5)-C(5') → σ∗S−Odelocalization in their anti-counterparts and to the existence of intramolecular 1,5-C(5')H⋅⋅⋅Ohydrogen bonds.Specific reactivity of β-keto sulfoxide and vinyl sulfoxide fragments present in 2-alkylidene-4-oxothiazolidine S-oxides offer a possibility for further regioselectivefunctionalization of the studied thiazolidinone derivatives. Another important issue of this..